Comparative Study of Hydrophobicity Parameters of Novel 5′‐Carbamates of Zidovudine

Raviolo, Mónica A.; Briñón, Margarita C.

doi:10.1081/jlc-200064145

Cited by 8 publications

(4 citation statements)

References 14 publications

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“…These studies were performed since they are important early requirements for novel compounds in drug research. Previously, we also have reported the lipophilicity and liposome permeability of 2–6 [ 7 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

Preformulation Studies of Zidovudine Derivatives: Acid Dissociation Constants, Differential Scanning Calorimetry, Thermogravimetry, X-Ray Powder Diffractometry and Aqueous Stability Studies

Raviolo

Briñón²

2011

Sci. Pharm.

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As part as of the preformulation studies of new 5′-OH derivatives of zidovudine, compounds 2–6, their acid dissociation constants, Differential Scanning Calorimetry (DSC) and Thermogravimetry (TG) curves, X-Ray Powder diffractograms and aqueous stability are reported. A sensitive technique such as differential scanning potentiometry was used to determine the pKa constants of the above mentioned compounds. In addition, pKa values were calculated from theoretical methods, and no significant differences with those of experimental ones were observed. X-Ray Powder Diffractometry data demonstrated that compounds 2–4 were crystalline while 5 and 6 were amorphous. DSC analysis indicated that all of them presented an exothermic decomposition peak above 150 °C which is accompanied by a weight loss in the respective TG curves. The stability of these compounds in aqueous medium at different pH values was investigated, using a validated High Performance Liquid Chromatography (HPLC) method, which demonstrated to be rapid, selective, sensitive, accurate and stability-indicating. Good recovery, linearity and precision were also achieved. For all compounds the aqueous hydrolysis followed a pseudo-first-order kinetics, depending on pH and the union existing between AZT and the associate moiety. The hydrolysis was catalyzed by hydroxide ion in the 7.4–13.2 pH range, while all compounds exhibited pH-independent stability from acidic to neutral media (pHs 1.0–7.4).

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Section: Introductionmentioning

confidence: 99%

Preformulation Studies of Zidovudine Derivatives: Acid Dissociation Constants, Differential Scanning Calorimetry, Thermogravimetry, X-Ray Powder Diffractometry and Aqueous Stability Studies

Raviolo

Briñón²

2011

Sci. Pharm.

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“…30 No correlation between in vitro antiviral potency of 2-7 and their lipophilicity was observed. This feature means that cell permeability by passive diffusion mechanism is not the key for the biological activity of these compounds.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and antiretroviral evaluation of derivatives of zidovudine

Raviolo

Trinchero-Hernández

Turk

2009

J. Braz. Chem. Soc.

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Uma série de novos carbamatos de zidovudina (AZT, 1) foi sintetizada, caracterizada e avaliada em relação a sua atividade anti-HIV e citotoxicidade. O grupo hidroxila da posição 5' do AZT foi derivatizado usando-se N, N'-carbonildiimidazol e diferentes aminas para gerar os respectivos 5'-O-carbamatos. Além disso, dois derivados já conhecidos foram sintetizados, um 5'-O-tosilato e um derivado tricíclico (AZT-Cycl), empregando-se métodos mais rápidos e simples do que os previamente reportados. Embora os novos derivados tenham apresentado menor toxicidade do que o AZT, essa redução na citotoxicidade foi concomitante com a marcada diminuição para inibir a replicação do vírus, com exceção do AZT-Cycl, o qual, mesmo apresentando IC 50 = 1 µmol L -1 , não demonstrou sinais de citotoxicidade com valores de CCID 50 (µmol L -1 ) > 1000.A series of zidovudine (AZT, 1) derivatives have been synthesized and their anti-HIV activity and cytotoxicity have been determined. The 5'-OH function of AZT was derivatized using N, N'-carbonyldiimidazole and different amine compounds leading to their 5'-O-carbamates. In addition, two known AZT derivatives 5'-O-tosylate and a tricyclic one (AZT-Cycl) were also obtained by a simpler procedure than those previously reported. Although these AZT derivatives were less toxic than AZT, their reduced cytotoxicity was concomitant with an inability to inhibit HIV-1 replication, except in the case of AZT-Cycl, which showed an IC 50 = 1 µmol L -1 without cytotoxicity with values of CCID 50 (µmol L -1 ) > 1000.

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“…21 Many nucleoside analogues with interesting biological properties have been developed by substitution at the 5 0 -O position of the NRTI with lipophilic chemical moieties linked by enzymatically hydrolysable functions such as ester and carbonate bonds. [19][20][21][22][23][24][25][26][27] The lipophilic character of the side chains at the 5 0 -O position should inuence their ability to cross the cell membrane by passive diffusion, which is a key feature in the absence of an active nucleoside transport system. [22][23][24]28,29 As stated by Parang et al, 20 more selective compounds can be designed by using the strategy of 5 0 -O-carbonates substitution.…”

Section: Introductionmentioning

confidence: 99%

“…[19][20][21][22][23][24][25][26][27] The lipophilic character of the side chains at the 5 0 -O position should inuence their ability to cross the cell membrane by passive diffusion, which is a key feature in the absence of an active nucleoside transport system. [22][23][24]28,29 As stated by Parang et al, 20 more selective compounds can be designed by using the strategy of 5 0 -O-carbonates substitution. Although clinical application of these approaches remains unknown, they hold the promise of becoming an important tool in the treatment of HIV infection and its related consequences.…”

Section: Introductionmentioning

confidence: 99%